Abstract Our long-term goal is to study the mechanisms of protein ubiquitination in the regulation of immune responses. Allergic asthma is a chronic inflammatory disease of the airways featured by the elevated serum immunoglogulin E (IgE) concentrations, airway hyperresponsiveness, excessive airway mucus production, lung eosinophilia, and airway remodeling. Differentiation of CD4+ T cells into T helper type 2 (Th2) cells renders them to produce Th2 type cytokines to drive asthmatic pathogenesis. The Th2-mediated immune responses are counterbalanced by tolerogenic mechanisms that keep the excessive reaction under control. One of the tolerance mechanisms involves regulatory T cells (Tregs) that limit the allergic responses. Transforming growth factor (TGF)- is critically involved in the generation and function of Tregs. Using both in vivo and in vitro model systems, we recently obtained preliminary data suggesting that the E3 ubiquitin ligase Itch plays an important role in the TGF--induced expression of Foxp3 and Treg- mediated proliferative inhibition. The new preliminary data allow us to formulate a hypothesis that the E3 ubiquitin ligase Itch is an important regulator in TGF- signaling, which is linked to TGF--induced Treg generation. Such regulation of T cell function underlies the mechanistic involvement of Itch in the development of Th2-mediated allergic responses. We plan to test this hypothesis by proposing detailed experiments to elucidate the intracellular signaling pathways modulated by Itch-induced protein ubiquitination, with a combination of both genetic and biochemical approaches. Such studies will help to design novel therapeutic interventions for allergic diseases.